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M Naoi

Publications and source records attributed to M Naoi.

At least 91 records · Page 5Linked to original sources
PubMed1995

N-methyl(R)salsolinol produces hydroxyl radicals: involvement to neurotoxicity.

Recently, (R)-1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [N-methyl-(R)salsolinol, NM(R)Sal] and 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion [DiMeDHIQ+] were found to cause a syndrome similar to parkinsonism in rodents. NM(R)Sal is produced in the brain by N-methylation of a naturally occurring catechol isoquinoline, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)salsolinol, (R)Sal], which is formed from dopamine. The mechanism of NM(R)Sal cytotoxicity to dopamine neurons was examined using in vitro experiments. NM(R)Sal was found to be nonenzymatically oxidized into DiMeDHIQ+, with concomitant formation of hydroxyl radicals. The oxidation and the radical production were completely inhibited by the antioxidants, ascorbic acid and reduced glutathione, and the radical formation was enhanced by Fe(II) and, to a less extent, by Fe(III). The oxidation of NM(R)Sal into DiMeDHIQ+ and the production of hydroxyl radicals may be essential for neurotoxicity to develop in dopamine neurons. The possible involvement of this catechol isoquinoline in the pathogenesis of Parkinson's disease is discussed.

Animals↗
PubMed1995

Dopamine-derived 1-methyl-6,7-dihydroxyisoquinolines as hydroxyl radical promoters and scavengers in the rat brain: in vivo and in vitro studies.

The effects of derivatives of dopamine-derived isoquinoline, (R)-1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [or (R)-salsolinol] on hydroxyl radical production were studied in vivo and in vitro. As reported previously, (R)-salsolinol is N-methylated in the brain into N-methyl-(R)-salsolinol, which is further oxidized into the 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion. Using in vivo microdialysis, we measured hydroxyl radical levels in the rat striatum by HPLC after derivatization to 2,3-dihydroxybenzoic acid with salicylic acid. (R)-Salsolinol and the isoquinolinium ion (40 and 200 microM) and N-methyl-(R)-salsolinol (200 microM) reduced in vivo radical formation, with reduction of dopamine catabolism. (R)-Salsolinol and the isoquinolinium ion reduced in vitro hydroxyl radical production from dopamine autoxidation. On the other hand, 40 microM N-methyl-(R)-salsolinol increased the hydroxyl radical level in the striatum, and the radical production by its autoxidation was confirmed in vitro. N-Methyl-(R)-salsolinol affected neither in vivo dopamine catabolism nor in vitro production of hydroxyl radicals from dopamine. These results show that (R)-salsolinol and N-methyl-(R)-salsolinol may be neuroprotective and neurotoxic, respectively, and thus might be in the pathogenesis of Parkinson's disease.

Animals↗
PubMed1994

Structural studies of condensation products of biogenic amines as inhibitors of tryptophan hydroxylase.

The effects of condensation products of dopamine and indoleamines on the activity of tryptophan hydroxylase (TPH) were evaluated to determine the structures associated with modulation of this enzyme activity. The compounds having a catechol structure, such as 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, markedly inhibited the activity of the enzyme prepared from the rat brain. The inhibition was non-competitive in terms of both the biopterin cofactor and the substrate L-tryptophan. Substitution on the one or two positions of catechol isoquinolines did not affect the inhibitory activity towards TPH. Among these compounds, a charged substance, 1,2[N]-dimethyl-6,7-dihydroxy-isoquinolinium ion, was an extremely potent inhibitor; the Ki values were 0.88 +/- 0.17 and 0.64 +/- 0.08 microM (mean +/- S.D.) in terms of the substrate and cofactor, respectively. By contrast, the condensation products of tryptophan and tryptamine with acetaldehyde scarcely affected TPH activities. 1-Methyl-1,2,3,4-tetrahydroisoquinoline, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ion (MPP+) were almost inactive. These results indicated that the catechol structure recognized and combined with TPH at a binding site different from that of the substrate or cofactor and the positive charge on the dopamine-derived substance enhanced the affinity to TPH. The selective inhibition of TPH by dopamine-derived catechol isoquinolines was discussed in relationship to the interactions between catecholamines, indoleamines and their metabolites in the brain under physiological and pathological conditions.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Inhibition of tryptophan hydroxylase by dopamine and the precursor amino acids.

Effects of dopamine and its precursor amino acids on the activity of tryptophan hydroxylase were examined. They inhibited the enzyme activity prepared from mastocytoma cells in terms of the biopterin cofactor and the substrate L-tryptophan. In relation to the biopterin, tryptophan hydroxylase was found to have two different kinetics, and dopamine inhibited the activity in a non-competitive way to both the components. Dopamine had the highest affinity to the enzyme, followed by L-DOPA and L-tyrosine, while D-tyrosine did not inhibit the activity. In terms of L-tryptophan, L-tyrosine, L-DOPA and dopamine inhibited the enzyme non-competitively and their affinity to the enzyme was in this order. These results indicate that the indoleamine metabolism may be regulated by catecholamines and their related amino acids in the brain.

Amino Acids↗
PubMed1994

Characterization of the in vivo action of (R)-salsolinol, an endogenous metabolite of alcohol, on serotonin and dopamine metabolism: a microdialysis study.

Using a microdialysis-HPLC technique in conscious rats, we examined the action of (R)-1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, (R)-salsolinol (R-Sal), a possible endogenous metabolite of alcohol, on serotonin (5-HT) and dopamine (DA) metabolism in four regions of the brain: the striatum, the substantia nigra, the hippocampus and the hypothalamus. Following 1 mM R-Sal perfusion, the dialysate level of 5-HT in the striatum markedly increased from non-detectable levels to 4259.2 +/- 617.5 nM, while DA increased from 3.4 +/- 0.9 nM to 206.0 +/- 56.5 nM. This increase was one order of magnitude larger in 5-HT than in DA. Conversely, the output of 5-hydroxyindoleacetic acid decreased markedly to non-detectable levels, while 3,4-dihydroxyphenylacetic acid and homovanillic acid outputs decreased below 40% of basal levels. These effects were dose-related to R-Sal (1 microM to 1 mM) and were confirmed also in 3 other brain regions. The R-Sal-induced responses in the striatum were observed even after pretreatment of 2 microM tetrodotoxin, a blocker of nerve-firing activity, via the dialysis membrane. The repetitive perfusion with 1 mM R-Sal into the striatum induced the reproducible response of 5-HT and DA. Furthermore, the potencies of 1 mM R-Sal to increase the output of 5-HT and DA were approximately 783.0-fold and 2.6-fold stronger, respectively, than those of the same dose of methamphetamine. The results suggest that R-Sal acts to stimulate a release of monoamines, 5-HT preferentially, with inhibition of monoamine oxidase and catechol-O-methyltransferase activities.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Binding of 1,2(N)-dimethyl-6,7-dihydroxy-isoquinolinium ion to melanin: effects of ferrous and ferric ion on the binding.

1,2(N)-Dimethyl-6,7-dihydroxy-isoquinolinium ion (N-methylsalsolinium ion) was found to bind to melanin, while N-methyl(R)salsolinol and (R)salsolinol did not. Two components with different affinity to melanin were found; the dissociation constant and maximal binding capacity were obtained as 2.1 and 79.4 nM, and 103 and 1336 pmol/mg melanin, respectively. The binding was enhanced by ferrous ion markedly and inhibited by 1-methyl-4-phenylpyridinium ion and ferric ion. N-Methylsalsolinium ion may be accumulated in dopamine neurons as melanin conjugate, which is regulated by ferric and ferrous ions.

Ferric Compounds↗
PubMed1994

Endogenous synthesis of N-methylnorsalsolinol in rat brain during in vivo microdialysis with epinine.

The in vivo metabolic pathway for the synthesis of N-methylnorsalsolinol, an analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was studied in the rat brain. N-Methyldopamine (epinine) was perfused at the striatum of the rat brain by in vivo microdialysis. N-Methylnorsalsolinol (NMNSAL) was identified in the brain dialysate after epinine perfusion using gas chromatography-selected-ion monitoring mass spectrometry (GC-SIM-MS). We demonstrated that NMNSAL could be synthesized from epinine with an aldehyde by the Piclet-Spengler condensation reaction in the rat brain.

Aldehydes↗
PubMed1994

Novel toxins and Parkinson's disease: N-methylation and oxidation as metabolic bioactivation of neurotoxin.

In human brains, a series of monoamine-derived 1,2,3,4-tetrahydroisoquinolines and the 6,7-dihydroxy derivatives has been identified. A tetrahydroisoquinoline was found to cause parkinsonism in monkey, but its toxicity was not so potent as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Two metabolic steps were found to increase cytotoxicity of isoquinolines. N-Methylation by a non-specific N-methyltransferase was proved by in vivo and in vitro experiments. The N-methylated compound was oxidized into N-methylisoquinolinium ion by monoamine oxidase from human brain mitochondria. The oxidation was proved by microdialysis in the rat brain. The isoquinolinium ion was more cytotoxic than the two metabolic precursors. N-Methylation of dopamine-derived 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines was detected by in vivo microdialysis in the rat striatum, and their presence in the human brain was confirmed by GC-MS. The metabolic bioactivation may be a general pathway to produce neurotoxins as the pathogenic agents of Parkinson's disease.

Adenosine Triphosphate↗
PubMed1994

Food-derived heterocyclic amines, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole and related amines, as inhibitors of monoamine metabolism.

The effects of heterocyclic amines, pyrolysis products of tryptophan, on monoamine metabolism were examined. Among these amines, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) are potent inhibitors of the enzymes related to amine metabolism. They inhibited type A monoamine oxidase more markedly than type B. After culture of a dopamine cell model, clonal pheochromocytoma PC12h cells, with Trp-P-1 activity of tyrosine hydroxylase was decreased by reduction of its affinity to the biopterin cofactor. Trp-P-1 and Trp-P-2 inhibited tryptophan hydroxylase competitively with the substrate and non-competitively with biopterin. These results suggest that food-derived heterocyclic amines may perturb the monoamine levels in the brain through the inhibition of the biosynthesis and metabolism of biogenic amines.

Amines↗
PubMed1994

Uptake of a neurotoxin-candidate, (R)-1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline into human dopaminergic neuroblastoma SH-SY5Y cells by dopamine transport system.

Uptake of catechol isoquinolines to dopamine cells was studied using human dopaminergic neuroblastoma SH-SY5Y cells. Only (R)-1,2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)-1,2-DiMeDHTIQ] was transported by dopamine uptake system, while (S)-1,2-DiMeDHTIQ, (R)- and (S)-1-methyl-6,7-dihydroxy-tetrahydroisoquinoline, and 1,2-dimethyl-6,7-dihydroxyisoquinolinum ion were not. Kinetical study showed that the uptake of (R)-1,2-DiMeDHTIQ followed the Michaelis-Menten equation, and the values of the Michaelis constant and the maximal velocity were obtained to be 102.6 +/- 36.9 microM and 66.0 +/- 2.8 pmol/min/mg protein. Dopamine was found to inhibit (R)-1,2-DiMeDHTIQ uptake competitively. These results suggest that the selective uptake by dopamine transporter may account for the specific neurotoxicity of (R)-1,2-DiMeDHTIQ to dopamine neurons.

Carrier Proteins↗
PubMed1994

A new metabolic pathway of L-threo-3,4-dihydroxyphenylserine, a precursor amino acid of norepinephrine, in the brain. Studies by in vivo microdialysis.

The metabolism and the effects of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) were studied in the rat brain striatum by in vivo microdialysis. In the brain L-threo-DOPS was metabolized by 3 different enzymes; aromatic L-amino acid decarboxylase, catechol-O-methyltransferase, and DOPS-aldolase. DOPS-aldolase was the main enzyme which metabolizes L-threo-DOPS. The amounts of the metabolites by L-amino acid decarboxylase (norepinephrine and its metabolites) were 0.4% of the total amounts of metabolites detected in the dialysate, while those by catechol-O-methyltransferase, 2.1%, and by DOPS-aldolase, 97.5%, after 100 min perfusion of L-threo-DOPS. L-threo-DOPS was found to increase extracellular levels of dopamine and serotonin, and to inhibit monoamine catabolism in the brain. Inhibition of DOPS-aldolase should improve its effectiveness as the supplement therapy of norepinephrine.

Animals↗
PubMed1994

Inhibition of tyrosine hydroxylase by a dopamine neurotoxin, 1-methyl-4-phenylpyridinium ion: depletion of allostery to the biopterin cofactor.

The effect of a dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+) on the activity of tyrosine hydroxylase was examined using the enzyme sample prepared from the rat striatum. Tyrosine hydroxylase had positive cooperativity to the biopterin cofactor and the Hill's coefficient was calculated as 1.79 +/- 0.23. MPP+ depleted this cooperativity and increased the Km value significantly. In the human brain the concentration of biopterin is unsaturated and the enzyme activity should be profoundly reduced by MPP+. Some of acute symptoms caused by MPP+ may be attributed to the inhibition of tyrosine hydroxylase.

1-Methyl-4-phenylpyridinium↗
PubMed1994

Inhibition of type A monoamine oxidase by 2(N)-methyl-6,7-dihydroxyisoquinolinium ions.

In the human brain, monoamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines and 1,2,3,4-tetrahydroisoquinolines have been identified and their enzymatic methylation into N(2)-methylisoquinolines has been also confirmed. N-methylated 6,7-dihydroxyisoquinolines were found to be oxidized into 6,7-dihydroxy-N-methylisoquinolinium ions. The effects of the isoquinolinium ions on type A and B monoamine oxidase were examined, using enzyme samples isolated from human brain synaptosomal mitochondria. 1,2-Dimethyl-6,7-dihydroxyisoquinolinium ion (N-methylsalsolinium ion) and 2-methyl-6,7-dihydroxyisoquinolinium ion (N-methylnorsalsolinium ion), were found to be potent inhibitors of type A monoamine oxidase. The inhibition was competitive to the substrate, while the isoquinolinium ions were much weaker inhibitors of type B and the inhibition was non-competitive to the substrate. Isoquinolinium ions without catechol structure, N(2)-methylisoquinolinium ion and 1,2-dimethylisoquinolinium ion also inhibited both type A and B monoamine oxidase. 1,2-Dimethylisoquinolinium was the most potent inhibitor among examined isoquinolines, followed by the N-methylsalsolinium ion. The activity-structure relationship of the isoquinolines with and without catechol structure was examined in terms of potency and selectivity of inhibition to type A and B monoamine oxidase. Catechol structure was found to increase the selectivity of inhibition to type A, as shown by comparison of N-methylsalsolinium ion with 1,2-dimethylisoquinolinium ion. N-Methylsalsolinium ion inhibited type A MAO more selectively than 1,2-dimethylisoquinolinium ion, which inhibited type A and type B with almost the sam values of the inhibitor constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗
PubMed1994

Striatal dopamine turnover during treadmill running in the rat: relation to the speed of running.

To evaluate the physiological action of striatal dopamine (DA) in exercise, rats were trained to run on a straight treadmill. Extracellular DA and its metabolites, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured by in vivo microdialysis, and striatal tissue tyrosine hydroxylase (TH) activity and monoamine oxidase (MAO) activity were measured using high performance liquid chromatography (HPLC) and spectrophotometer. DA turnover was increased by running, and the increase in DOPAC and HVA was closely related to the speed of running, while the increase in DA had no relationship to the speed. The threshold for the increase in DA, DOPAC, and HVA was between 300 and 660 cm/min. Striatal tissue TH activity was elevated up to 135% of basal values after the rats were trained for 7 days to run at 1800 cm/min. Just after running for 20 min, there was a further increase to 180%. These values became 150% and 90% of basal values at 2 h and 6 h, showing a similar time course as DA detected by microdialysis. MAO-B activity increased up to 160% of basal values after 7 days training but decreased to 130% and 110% just after and 2 h after running, then increased to 145% 6 h after running. MAO-A showed a similar variation as MAO-B. These data suggest that both the synthesis and metabolism of DA have a close relationship with physical exercise and might contribute to adjusting extracellular DA levels within an adequate range in response to exercise intensity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Expression of stratified squamous epithelia-type cytokeratin by canine mammary epithelial cells during tumorigenesis: type I (acidic) 57 kilodalton cytokeratin could be a molecular marker for malignant transformation of mammary epithelial cells.

Two monoclonal antibodies (MAbs) were established in 20 clones of MAbs generated against cytokeratin fraction extracted from canine squamous cell carcinoma to investigate the expression of intermediate filament proteins during tumorigenesis. These MAbs were confirmed to react with purified cytokeratin by ELISA. One monoclonal antibody, MAb32 reacted all layers of epidermis except the cornified layer and mammary myoepithelial cells but not any epithelial cells. Another antibody named MAb24 exclusively reacted the basal monolayer of epidermis, the stratum germinativum. Any positive reactions with MAb24 were not detected in normal mammary gland. From the analysis by two-dimensional gel electrophoresis followed by immunoblotting, it was revealed that MAb24-recognizing cytokeratin subunit gave a molecular weight of 57 kilodalton and a isoelectric-pH value of pI5.1, indicating type I (acidic) cytokeratin. In intraductal papillomas developed in canine mammary glands, most tumor cells were positively stained with MAb32 in addition of myoepithelial cells while no positive reaction with MAb24 was seen. In ductal carcinomas, MAb24-positive cytokeratin was begun to express by tumor cells with positive reaction of MAb32 where these cells showed infiltrative growth into the stroma. We therefore proposed that 57 kilodalton-type I cytokeratin was a molecular marker for malignant transformation in canine mammary tumor and these antibodies could be useful tools to investigate the change of cytokeratin expression during tumorigenesis.

Adenofibroma↗
PubMed1994

Immunohistochemical examination of neural cell adhesion molecule (NCAM), tenascin and fibronectin on the development of cartilaginous tissue in canine mammary mixed tumors.

The expression of neural cell adhesion molecule (NCAM), tenascin and fibronectin during cartilage-like tissue formation in canine mammary mixed tumor was immunohistochemically examined. Mirror-image serial sections revealed that proliferating myoepithelial cells simultaneously expressed these adhesion molecules where no cartilage-like tissue and no expression of cartilage-specific type II collagen were observed. With the formation of cartilaginous tissue, positive signals of these adhesion molecules decreased in chondroblast-like cells, the cartilaginous tissue was hyalinized and mature chondrocyte-like cells no longer expressed these cell adhesion molecules. NCAM, tenascin and fibronectin, therefore, may play crucial roles on the proliferation of myoepithelial cells and the subsequent development of cartilaginous tissue in canine mammary mixed tumor.

Amino Acid Sequence↗
PubMed1994

[The effect of droxidopa on the monoamine metabolsim in the human brain].

Droxidopa (L-threo-3,4-dihydroxyphenylserine) is an artificial amino acid, which is used to supplement noradrenaline (NA) in neurodegenerative disorders. Droxidopa is decarboxylated into NA by aromatic L-amino acid decarboxylase in the brain, but its effects on other monoamine neurotransmitters, such as dopamine (DA) and serotonin (5-HT) have not been systematically examined. The monoamine metabolism has been suggested to interact with each other in the brain, and by analysis of the cerebrospinal fluid, L-DOPA, a precursor amino acid used for supplement of DA, was found to inhibit serotonin synthesis in the brain. To examine the effects of droxidopa on the monoamine metabolism, the intraventricular fluid of the patients administered with droxidopa and L-DOPA was analyzed. The levels of monoamines, their precursor amino acids, and their metabolites were compared between the patients administered with L-DOPA. In the patients administered by droxidopa and L-DOPA, droxidopa was shown to increase the concentrations of monoamines (NA, DA and 5-HT), but the difference was not statistically significant by comparison with those treated by L-DOPA alone. The metbolites of DA and 5-HT by monoamine oxidase, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) were also found to increase by droxidopa administration. On the other hand, the metabolites of NA and DA by catechol-O-methyltransferase (COMT), normetanephrine (NMN) and 3-methoxytyramine (3-MT), decreased in the patients treated with droxidopa and L-DOPA compared with the patients administered with L-DOPA alone and control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗